Use of delta5-androstene-3beta ol-7,17-dione in the treatment of lupus erythematosus

ABSTRACT

Lupus erythematosus can be treated by administering therapeutic amounts of Δ5-androstene-3β-ol-7,17-dione and metabolizable precursors thereof, such as Δ5-androstene-3β-acetoxy-7,17-dione, which are readily metabolized in vivo to Δ5-androstene-3β-ol-7,17-dione but are not appreciably metabolizable in vivo to androgens, estrogens or dehydroepiandrosterone. Such treatment can be prophylactic, ameliorative or curative in nature.

FIELD OF THE INVENTION

[0001] This invention broadly relates to treatment strategies for lupuserythematosus. More specifically, the invention relates to prophylactic,ameliorative and curative drug therapies for lupus erythematosus.

BACKGROUND

[0002] Lupus erythematosus is an autoimmune disorder which may, but doesnot always, affect many different organ systems in an affectedindividual. Lupus erythematosus (hereinafter “lupus”) may affect theheart, lungs, skin, joints, kidneys, nervous system, lymph gland system,blood cells and/or blood vessels. Certain forms of lupus affect only orpredominantly the skin. These forms of lupus are the most visiblemanifestations of the disease.

[0003] The immune system of the body is a complex and elaboratemechanism of protection from foreign substances. The immune systemprovides resistance to foreign cells and substances (e.g., bacteria orvirus) that may cause injury, as well as searching out abnormal cells(e.g., cancerous cells) within the body for destruction. The invading orabnormal cells are neutralized by the immune system humoral and cellularcomponents, including lymphocytes, antibodies, mediating (regulatingsuch as Lymphokines) systems, and effector (cytotoxic) cells. As anexample. the immune system can recognize the invading or abnormal cells(antigens) within the body and produce antibodies (proteins) whichattach to the recognized antigens, leading to their removal.Autoimmunity occurs when the immune system produces antibodies to normalcells in the body. This produces inflammation of normal tissue,resulting in damage and loss of function. In other instances, antibodiesattach to antigens within the blood plasma to form immune complexes thatmay be deposited in normal tissue resulting in inflammation and damage.

[0004] Women are more susceptible to lupus than men. Over 90% of lupuspatients are females aged 13-40 years. Laboratory tests for the presenceof lupus include the LE Cell Test, the Anti-Nuclear Antibody Test, andthe test for Anti-DNA-Antibodies. Lupus is, however, often recognized byparticular clinical manifestations including: (i) arthritis (occurringin 90-95% of persons with systemic lupus), (ii) skin changes, such as aphotosensitive induced “butterfly” rash across the bridge of the nose,across the cheeks and/or beneath the eyes, and/or red, raised and scalypatches, known as discoid lupus, anywhere on the body (occurring in75-80% of persons with lupus), (iii) hematologic abnormalities, such asanemia, leukopenia, and thrombocytopenia (occurring in about 50% ofpersons with lupus), (iv) kidney impairment (occurring in about 50% ofpersons with lupus), (v) heart or lung disease, such as an irritation ofthe heart or lung lining causing pericarditis or pleurisy (occurring inabout 30% of persons with lupus), and (vi) neuropsychiatric changes(occurring in about 10% to 20% of persons with lupus).

[0005] Etiology

[0006] Lupus erythematosus can be divided into subsets which may or maynot have overlapping characteristics: discoid lupus, subacute cutaneouslupus, drug-induced lupus and systemic lupus. Patients in whom thedisease seems to be confined to the skin are differentiated from thosewith systemic or “disseminated” involvement.

[0007] Discoid lupus, also called chronic discoid lupus or chroniccutaneous lupus produces lesions over the face, but sometimes spreadmore extensively across the body. The lesions are usually wellcircumscribed, disk-like plaques of scaling erythema, tending to clearcentrally with scarring, depigmentation and atrophy. Photosensitivity isa common feature but may be absent. Roughly 80% to 90% of patients withdiscoid lupus lesions will not develop any signs and symptoms ofsystemic lupus.

[0008] Subacute cutaneous lupus produces wide spread skin lesions overthe trunk and extremities of the patient. The lesions are apt to be lessdiscrete than those of discoid lupus, more widespread, with temporarydepigmentation and telangiectasia without scaring or atrophy. Loss ofhair without scaring is common, and mild systemic disease, especiallyinvolving the joints, accompanied by fever and malaise are oftenpresent.

[0009] Another distinct subset of lupus is that associated with reactionto certain drugs, appropriately known as drug induced lupus. Seriousorgan involvement is rare and prognosis for this subset of lupus isexcellent, provided the disease is recognized and the offendingmedication discontinued.

[0010] Systemic lupus is a chronic autoimmune disease that often has arelapsing course. The primary therapeutic approach for systemic lupus isto achieve and maintain adequate suppression of the disease with minimaldrug mediated side effects. Evaluation of specific symptoms and clinicalfindings establish the type and extent of organ involvement and overalldisease activity. There are two basic goals of drug treatment for lupus.The first goal is to reduce inflammation within the affected tissues.The second goal is to identify and suppress the specific abnormalitiesof the immune system that are considered responsible for tissueinflammation. The overall therapeutic plan generally groups lupusmanifestations into four broad categories based on primary treatmentmodality used for initial treatment.

[0011] Fever, joint pain (arthralgias), arthritis, and serositis(pleurisy or pericarditis) can often be managed effectively by theadministration of nonsteroidal, anti-inflammatory drugs (NSAIDs), suchas aspirin, salisylates, ibuprofin, naproxen, clinoril, oxaprozin andtolmetin. The most common side-effects include gastrointestinalcomplaints and the potentiation of peptic ulcers. Acetaminophenderivatives can be safely taken with NSAIDs for added pain relief.

[0012] Cutaneous features of systemic lupus are usually most effectivelymanaged with antimalarial drugs, such as hydroxychloroquine, chloroquineand quinacrine. Due to the high rate of cutaneous disease relapse andthe safety of low-dose therapy, anti-malarial drug is usually prescribedon an indefinite basis for patients displaying lupus skin conditions.Retinoids such as istretinoin (Acutane™) and etretinate (Acitretinz™)demonstrate beneficial results when given orally, with reduction oflesions refractory to traditional antimalarial drug therapy.

[0013] More serious organ involvement is generally treated by theadministration of a corticosteroid, given orally or intravenously.Prednisone is the most commonly used oral corticosteroid. When oraladministration of steroids proves ineffective, intravenous methylprednisolone pulse therapy (high dose) is often used in the treatment oflupus nephritis and other serious non-renal manifestations, such ashemolytic anemia, central nervous system inflammation (cerebritis),life-threatening low-platelet counts, and severe pleuropericarditis.Mild androgenic compounds such as Danazol™ and dehydroepiandrosterone(DHEA) have also been used in controlling immune thrombocytopenia andsevere hemolytic anemia.

[0014] DHEA has also been reported to be effective for treating variousmanifestations of systemic lupus, with a focus upon the reported abilityof DHEA to affect the hormonal and immune systems.

[0015] Immunosuppressive drugs are a fourth group used in treatment ofsystemic lupus. These drugs are employed when corticosteroid therapy isineffective or intolerable for the patient. Immunosuppressive drugsinclude azathirprine (Imuran™), cyclosporin A (Sandimmune™), alkylatingagents (nitrogen mustards, cyclophosphamide, and chlorambucil), andmethotrexate. These drugs are sometimes used in combination withcorticosteroids.

[0016] The above described treatment regimens for lupus often meet withlimited success. Hence, the search continues for alternative treatmentsfor lupus.

SUMMARY OF THE INVENTION

[0017] The invention is directed to the prophylactic, ameliorative andcurative treatment of lupus erythematosus by administeringΔ5-androstene-3β-ol-7,17-dione and precursors thereof which are readilymetabolized in vivo to Δ5-androstene-3β-7,17-dione but essentiallyincapable of being metabolized to androgens, estrogens ordehydroepiandrosterone.

DETAILED DESCRIPTION OF THE INVENTION INCLUDING A BEST MODE

[0018] Lupus erythematosus can be treated by administering therapeuticamounts of Δ5-androstene-3β-ol-7,17-dione and precursors thereof whichare readily metabolized in vivo to Δ5-androstene-3β-ol-7,17-dione butessentially incapable of being metabolized to androgens, estrogens ordehydroepiandrosterone, such as Δ5-androstene-3β-acetoxy7,17 dione andother 3β esters thereof.

[0019] Such treatment can be prophylactic, ameliorative or curative innature.

[0020] Without intending to be bound by any theory, it is believed thatΔ5-androstene-3β-ol-7,17 dione is effective for preventing, amelioratingand curing lupus erythematosus by modulating appropriate aspects of theaberrantly functioning immune system responsible for the onset and/orcontinuation of lupus erythematosus (i.e., increasing depressed and/ordecreasing hyperactive aspects of the system), particularly with respectto the production of appropriate concentrations of IL-2.

[0021] Δ5-Androstene-3β-ol-7,17-dione

[0022] Δ5-androstene-3β-ol-7,17 dione is a derivative ofdehydroepiandrosterone (DHEA) which does not appreciably stimulate,increase or otherwise enhance the production of sex hormones.Δ5-androstene-3β-ol-7,17 dione is commercially available from a numberof sources including Steraloids, Inc. of Wilton, N.H. A number ofprocedures are available for synthesizing Δ5-androstene-3β-ol-7,17 dionefrom DHEA, with one such procedure described in U.S. Pat. No. 5,296,481.

[0023] Precursors of Δ5-androstene-3β-ol-7,17-dione, which areessentially incapable of being metabolized to androgens, estrogens ordehydroepiandrosterone, may also be usefully employed in the treatmentof lupus erythematosus. Such precursors are readily metabolized in vivoto the active Δ5-androstene-3β-ol-7,17-dione. One example of such ametabolizable precursor is the commercially availableΔ5-androstene-3β-acetyl-7,17-dione. The 3β-acetyl group is readilyhydrolyzed in vivo by esterases located in the blood and various bodytissue to produce the active Δ5-androstene-3β-ol-7,17-dione, and isbelieved to be less susceptible to oxidation at the 3β-position duringthe manufacturing process relative to Δ5-androstene-3β-ol-7,17-dione.

[0024] Administration

[0025] Administration Route

[0026] The Δ5 Androstene-3β-acetoxy-7,17-dione can be administered byvirtually any of the commonly accepted practices for the administrationof pharmaceutical preparations including specifically, but notexclusively, intravenous injection, mucosal administration, oralconsumption, ocular administration, subcutaneous injection, transdermaladministration, etc.

[0027] Mucosal administration of AS Androstene-3β-acetoxy-7,17-dioneincludes such routes as buccal, endotracheal, inhalation, nasal,pharyngeal, rectal, sublingual, vaginal, etc. For administration throughthe buccal/inhalation/sublingual I pharyngeal/endotracheal mucosa, thesteroid may be formulated as an emulsion, gum, lozenge, spray, tablet oran inclusion complex such as cyclodextrin inclusion complexes. Nasaladministration is conveniently conducted through the use of a sniffingpower or nasal spray. For rectal and vaginal administration the steroidmay be formulated as a cream, douch, enema or suppository.

[0028] Oral consumption of the steroid may be effected by incorporatingthe steroid into a food or drink, or formulating the steroid into achewable or swallowable tablet or capsule.

[0029] Ocular administration may be effected by incorporating thesteroid into a solution or suspension adapted for ocular applicationsuch as drops or sprays.

[0030] Intravenous and subcutaneous administration involvesincorporating the steroid into a pharmaceutically acceptable andinjectable carrier.

[0031] For transdermal administration, the steroid may be convenientlyincorporated into a lipophilic carrier and formulated as a topical cremeor in an adhesive patch.

[0032] Dose Rate

[0033] The range of dosages and dose rates effective for achieving thedesired biological properties and characteristics may be determined inaccordance with standard industry practices. These ranges can beexpected to differ depending upon whether the desired response is theprophylactic, ameliorative or curative treatment of lupus erythematosus,the type of lupus and the severity of symptoms.

Experimental

[0034] Experiment 1

[0035] (Preparation of Δ5 Androstene-3,β-acetoxy-7,17-dione)

[0036] Step One:

[0037] (Preparation of Δ5 Androstene-3-acetoxy-17-one)

[0038] A suitable, three-necked, round-bottom flask equipped with anoverhead stirrer, reflux condenser, solids addition funnel and 110-volttemperature controller was charged with a mixture of dichloromethane (90ml), glacial acetic acid (150 ml), and acetic anhydride (250 ml). To themixture was added dehydroepiandrosterone (0.20 moles) purchased fromSteraloids, Inc. of Wilton, N.H. The mixture was stirred to dissolve thesolid dehydroepiandrosterone, and anhydrous sodium acetate (35.0 g)added. The resulting mixture was heated at 75° C. with stirring for 3hours to complete the reaction.

[0039] The reaction mixture was poured into one liter of water and theresulting slurry stirred at room temperature for 2 hours. The organicdichloromethane layer was separated from the aqueous layer, and theaqueous layer extracted once with 50 ml of fresh dichloromethane. Thecombined organic dichloromethane extract was washed with water,saturated sodium bicarbonate solution (until neutral), and water. Theresulting washed organic dichloromethane extract was evaporated underreduced pressure to a volume of 40 ml. Methanol (100 ml) was added tothis concentrated extract and the resulting solid mass was cooled at 0°C. in a refrigerator for 2 hours.

[0040] The resulting solid white product was collected by vacuumfiltration on a Buchner funnel and the filter cake air dried on thefunnel to form a first crop of product weighing 50.5 g. The filtratemother liquor was concentrated by evaporation under reduced pressure,and cooled at 0° C. in a refrigerator. The resulting solid white productwas collected by vacuum filtration on a Buchner funnel and the filtercake air dried on the funnel to form a second crop of product weighing10.2 g. The filtrate mother liquor from the second crop of product wasdiluted with water and the mixture was cooled at 0° C. in arefrigerator. The resulting solid white product was collected by vacuumfiltration on a Buchner funnel and the filter cake air dried on thefunnel to form a third crop of product weighing 4.2 g.

[0041] The first, second and third crops of product were combined toproduce a total of 64.9 grams of Δ5 androstene-3-acetoxy-17-one.

[0042] Theoretical yield=66.1 g

[0043] First crop yield=50.5 g (76.4%)

[0044] Second crop yield=10.2 g (15.4%)

[0045] Third crop yield=4.2 g (6.4%)

[0046] Step Two:

[0047] (Preparation of Crude Δ5 Androstene-3-acetoxy-7,17-dione)

[0048] A suitable, three-necked, round-bottom flask equipped with anoverhead stirrer, reflux condenser, addition funnel, thermometer,mineral oil filled bubbler and a gas inlet tube connected to a nitrogencylinder, was charged with acetone (3.5 L) and cyclohexane (3.5 L). 1.51moles of the Δ5 Androstene-3-acetoxy-17-one prepared in Step One wasadded to the flask with stirring to dissolved the solid Δ5Androstene-3-acetoxy-17-one. 2.48 moles of solid sodium metaperiodateand water (1.1 L) were added to the stirred solution. 14.75 moles of a70% aqueous solution of t-butyl hydroperoxide (2.0 L) was added to theflask through the addition funnel over a one-half hour period.

[0049] Over the first hour, the reaction mixture temperature rose from20° C. to 32° C. Tap water was added to an external cooling bath and thereaction mixture temperature returned to 20° C. The reaction mixture wasconstantly vigorously stirred throughout the experiment, and thereaction judged to be complete after 48 hours by TLC monitoring of thedisappearance of starting material. The mixture changed from a whiteslurry to a light yellow slurry over the course of the reaction.

[0050] The reaction mixture was poured into a stirred ice/water mixture(12 kg ice and 8 L water). Potassium sulfite (3 L of a 45% aqueoussolution) was then added to the diluted reaction mixture over 30 minutes(100 mL/min) to destroy any remaining oxidant. The diluted mixture wasstirred for an additional 2 hours, with ice added as needed to maintainthe mixture at 15° C.

[0051] The resulting diluted, cooled reaction mixture was transferred toa suitable container and ethyl acetate (3 L) was added to dissolve andextract the product. The resultant mixture was stirred for one-half hourand then allowed to stand so as to permit the organic and aqueous layersto separate. The aqueous layer was examined by TLC, found to contain noproduct, and discarded. The solids containing organic layer wastransferred to a separatory finnel, washed with water (3×1.5 L), thenwashed with a saturated salt solution (1×1.5 L). The washed organiclayer was dried over sodium sulfate (300 g), with decolorizing carbon(100 g) added. The resulting organic slurry was filtered through aceramic Buchner funnel containing a 0.5 inch Celite pad (100 g). Thefilter cake was washed with ethyl acetate (2×150 ml) and the washingcombined with the filtrate.

[0052] The combined organic filtrate was concentrated in vacuo to neardryness to produce an off-white semi-solid. The semi-solid was suspendedin methanol (400 ml) and again concentrated in vacuo to near dryness toproduce a semi-solid. The semisolid was slurried in methanol (600 ml)and the slurry stirred for 2 hours at ambient temperature. The solidproduct was collected by filtration on a ceramic Buchner funnel, and thesolids washed with cold (5° C.) methanol (2×75 ml). The solid productwas dried at 65° C. for 48 hours under high vacuum (<1 mm Hg vacuum).The process yielded 232 grams of crude solid Δ5Androstene-3-acetoxy-7,17-dione.

[0053] Theoretical yield=521 g

[0054] Actual yield=232 g (44.5%)

[0055] Step Three:

[0056] (Preparation of Purified Δ5 Androstene-3-acetoxy-7,17-dione)

[0057] Method A:

[0058] A 500 ml round bottom flask equipped with a magnetic stirrer wascharged with 25.0 grams of the crude Δ5 Androstene-3-acetoxy-7,17-dioneprepared in Step Two and 300 ml of a mixture of methanol and ethylacetate (1:1, v/v). The magnetic stirrer was activated and the slurrystirred at room temperature until the crude Δ5Androstene-3-acetoxy-7,17-dione was completely dissolved in the solventmixture to form a first solution. A freshly prepared 10% aqueoussolution of sodium bicarbonate (25 ml) was added over 10 minutes to thereaction mixture. The resulting milky mass was stirred at roomtemperature for 2.5 hours.

[0059] The reaction mixture was concentrated at room temperature underreduced pressure to 100 ml volume. The concentrated reaction mixture wasdiluted with 200 ml of ice water and stirred for 30 minutes at 0-5° C.The precipitated solids were collected on a ceramic Buchner funnel, andthe aqueous filtrate reserved for additional product recovery. Thesolids on the funnel were washed with water (until neutral), andmethanol (2×30 ml), with the methanol washing also reserved for productrecovery. The first crop of solids was dried overnight under vacuum togive 18.0 g of purified product.

[0060] The aqueous filtrate from the first crop of solids was extractedwith ethyl acetate (100 ml), and the separated organic extract waswashed with water. The solvent of the washed extract was removed underreduced pressure to produce a solid product. This solid product wasdissolved in the methanol washing from the first crop of solids, and thesolution concentrated to 30 ml volume. Upon cooling the concentrate, asolid precipitate product formed which was collected by vacuumfiltration. The second crop of solids was air dried to give 5.2 g ofpurified product.

[0061] The mother liquor filtrate from the second crop of solids wasdiluted with water and cooled. The resulting white solid precipitate wascollected by vacuum filtration, and dried overnight at room temperatureto give a third crop of 1.0 g of purified product.

[0062] The process yielded a total of 24.2 grams of purified solid Δ5Androstene-3-acetoxy-7,17-dione.

[0063] Theoretical recovery=25.0 g

[0064] Actual recovery=24.2 g (96.8%)

[0065] Method B:

[0066] A suitable round bottom flask equipped with a magnetic stirrerwas charged with 1.0 gram of the crude Δ5Androstene-3-acetoxy-7,17-dione prepared in Step Two and 10 ml ofacetone. The magnetic stirrer was activated and the slurry was stirredat room temperature until the crude Δ5 Androstene-3-acetoxy-7,17-dionewas completely dissolved in the acetone. To this solution was added 2.0g of aluminum oxide basic. The resulting slurry was stirred at roomtemperature for 1 hour, then filtered through a bed of Celite. Thecollected solids and Celite bed were washed once with 5 ml of acetone,and the washing combined with the filtrate. The combined filtrate wasevaporated to near dryness under reduced pressure to produce a solidproduct. The solid product was dissolved in a mixture of methanol andisopropyl ether (8:2, v/v) with heating. This solution was cooled at0-5° C. for 30 minutes, resulting in precipitation of a white product.The precipitated solid was collected by vacuum filtration and air driedto give 0.9 grams of purified solid Δ5 androstene-3-acetoxy-7,17-dione.

[0067] Theoretical recovery=1.0 g

[0068] Actual recovery=0.9 g (90.0%)

I claim:
 1. A treatment method comprising treating a patient in need ofsuch treatment with an effective autoimmune disorder ameliorative amountof a steroid selected from Δ5-androstene-3β-ol-7,17-dione andmetabolizable precursors thereof incapable of being appreciablymetabolized to androgens, estrogens or dehydroepiandrosterone.
 2. Thetreatment method of claim 1 wherein the method comprises treating apatient with an effective autoimmune disorder ameliorative amount of asteroid selected from Δ5-androstene-3β-ol-7,17-dione andΔ5-androstene-3β-acetoxy-7,17-dione.
 3. The treatment method of claim 1or 2 wherein the method of treating a patient comprises treating a lupuserythematosus-affected human patient.
 4. The treatment method of claim 3wherein the method of treating a lupus erythematosus affected humanpatient comprises treating a human patient affected by systemic lupuserythematosus.
 5. The treatment method of claim 3 wherein the method oftreating a lupus erythematosus affected human patient comprises treatinga human patient afflicted with lupus erythematosus-related tissueinflammation.
 6. The treatment method of claim 3 wherein the method oftreating a lupus erythematosus affected human patient in need of suchtreatment comprises treating a patient diagnosed with lupuserythematosus.
 7. The treatment method of claim 4 wherein the method oftreating a systemic lupus erythematosus affected human patient comprisestreating a human patient afflicted with systemic lupus erythematosus. 8.The treatment method of claim 4 wherein the method of treating asystemic lupus erythematosus affected human patient comprises treating ahuman patient diagnosed with systemic lupus erythematosus.
 9. Atreatment method comprising administering an effective preventativeamount of a steroid selected from Δ5-androstene-3β-ol-7,17-dione andmetabolizable precursors thereof incapable of being appreciablymetabolized to androgens, estrogens or dehydroepiandrosterone, to ananimal susceptible to lupus erythematosus.
 10. The treatment method ofclaim 9 wherein the method of administering an effective preventativeamount of a steroid comprises administering an effective preventativeamount of a steroid selected from Δ5-androstene-3β-ol-7,17-dione andΔ5-androstene-3β-acetoxy-7,17-dione.
 11. The treatment method of claim 9or 10 wherein the method of administering an effective preventativeamount of a steroid to an animal susceptible to lupus erythematosuscomprises administering the steroid to a human susceptible to lupuserythematosus.
 12. The treatment method of claim 11 wherein the methodof administering an effective preventative amount of a steroid to ahuman susceptible to lupus erythematosus comprises administering thesteroid to a human substantially free of lupus erythematosus-relatedtissue inflammation but previously afflicted with lupus erythematosus-related tissue inflammation.
 13. The treatment method of claim 11wherein the method of administering an effective preventative amount ofa steroid to a human susceptible to lupus erythematosus comprisesadministering the steroid to a human substantially free of lupuserythematosus-related tissue inflammation but previously diagnosed withlupus erythematosus -related tissue inflammation.
 14. A treatment methodcomprising treating a patient in need of such treatment with aneffective autoimmune disorder curative amount of a steroid selected fromΔ5-androstene-3β-ol-7,17-dione and metabolizable precursors thereofincapable of being appreciably metabolized to androgens, estrogens ordehydroepiandrosterone.
 15. The treatment method of claim 14 wherein themethod comprises treating a patient with an effective autoimmunedisorder curative amount of a steroid selected fromΔ5-androstene-3β-ol-7,17-dione and Δ5-androstene-3β-acetoxy-7,17-dione.16. The treatment method of claim 14 or 15 wherein the method oftreating a patient comprises treating a lupus erythematosus-affectedhuman patient.
 17. The treatment method of claim 16 wherein the methodof treating a lupus erythematosus affected human patient comprisestreating a human patient affected by systemic lupus erythematosus. 18.The treatment method of claim 16 wherein the method of treating a lupuserythematosus affected human patient comprises treating a human patientafflicted with lupus erythematosus-related tissue inflammation.
 19. Thetreatment method of claim 14 or 15 wherein the method of treating apatient in need of such treatment comprises treating a human patientdiagnosed with lupus erythematosus.
 20. The treatment method of claim 14or 15 wherein the method of treating a patient comprises treating ahuman patient afflicted with lupus erythematosus.
 21. The treatmentmethod of claim 14 or 15 wherein the method of treating a patientcomprises treating a human patient diagnosed with systemic lupuserythematosus.